Synthesis of large ring macrocycles (12-18) by recyclable palladiumComplexed dendrimers on silica gel catalyzed intramolecular cyclocarbonylation reactions

Article abstract of DOI:10.1002/chem.200601724

Intramolecular cyclocarbonylation reactions with palladium-complexed dendrimers on silica gel as catalysts are very effective for the synthesis of twelveto eighteen-membered ring macrocycles. This process can tolerate a wide variety of functional groups,

Full text of DOI:10.1002/chem.200601724

DOI: 10.1002/chem.200601724
Synthesis of Large Ring Macrocycles (12–18) by Recyclable Palladium-
Complexed Dendrimers on Silica Gel Catalyzed Intramolecular
Cyclocarbonylation Reactions
Shui-Ming Lu and Howard Alper*[a]
Abstract: Intramolecular cyclocarbonylation reactions with palladium-complexed
dendrimers on silica gel as catalysts are very effective for the synthesis of twelve-
to eighteen-membered ring macrocycles. This process can tolerate a wide variety
of functional groups, including halide, ether, ketone, and ester. The heterogeneous
dendritic catalysts facilitate excellent substrate reactivity, affording oxygen-, nitro-
gen-, or sulfur-containing tricyclic heterocycles in 70–92% yields. Importantly,
these systems are easily recovered by simple filtration and reused several times
with only a slight loss of activity.
Keywords:
dendrimers
heterogeneous catalysis · palladium
carbonylation
· heterocycles
·
·
Introduction
Dendrimers are regular hyperbranched and well-defined
macromolecules with a number of potential applications in
chemistry, biology, and materials science.[4] One of the most
interesting applications of dendrimers is the use of their
transition-metal complexes for catalysis.[5] As an interface
between homogeneous and heterogeneous catalysts, metal-
lodendrimers represent a fascinating field of research be-
cause they allow the facilitated recovery and reuse of the
catalysts, a beneficial feature for reaction efficiency, econo-
my, and environmental concern. Soluble dendritic catalysts
are widely applied to a variety of organic reactions, includ-
ing hydrogenation,[6] oxidation,[7] hydrovinylation,[8] hydroly-
sis,[9] the Heck,[10] Sonogashira,[11] Suzuki,[12] and Henry reac-
tions,[13] Kharash addition,[14] Stille coupling,[15,16] Knoevena-
gel condensation, Michael addition,[16] and the asymmetric
addition of diethylzinc to aldehydes.[17] However, relatively
few examples involve dendritic catalysts on a solid sup-
port.[18] Recently, we found that dendrimer complexes on
silica gel or a resin show high activity for carbonylation and
hydroformylation reactions.[19] These systems can be easily
recovered by simple filtration in air and reused without loss
of activity. To our knowledge, there are no reports on intra-
molecular cyclocarbonylation reactions with recyclable pal-
ladium-complexed dendrimers on silica gel to form oxygen-,
nitrogen-, or sulfur-containing large ring-fused heterocycles.
It is anticipated that this protocol could have considerable
potential for assembling the desired cyclic compounds. We
now demonstrate that heterogeneous dendrimer–palladium
complexes are very effective catalysts for the synthesis of
Heterocycles are of great synthetic interest since they con-
stitute important structural motifs in biologically active nat-
ural products, as well as for pharmaceuticals and agrochemi-
cals.[1] As a result, much effort has been devoted to the de-
velopment of novel and efficient strategies for the prepara-
tion of cyclic compounds. Among the various options, transi-
tion-metal catalysis has attracted increasing attention. In
particular, carbonylation reactions provide a powerful tool
for the construction of complex polycyclic systems that are
generally not accessible by classical methods.[2] However,
the synthesis of large ring-fused heterocycles still poses a
significant challenge. Furthermore, while homogeneous cata-
lytic processes often display excellent activity, a major draw-
back is the tedious separation of the catalysts from the reac-
tion products that in turn may lead to economical or ecolog-
ical problems especially in the case of expensive and/or
toxic metal complexes.[3] Therefore, it is highly desirable to
develop innovative approaches for the design of recoverable
and reusable catalysts.
[a] Dr. S.-M. Lu, Prof. Dr. H. Alper
Centre for Catalysis Research and Innovation
Department of Chemistry, University of Ottawa, 10 Marie Curie
Ottawa, Ontario, K1N6N5 (Canada)
Fax : (+1)613-562-5271
E-mail: howard.alper@uottawa.ca
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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FULL PAPER
twelve- to eighteen-membered ring macrocycles in good to
excellent yields.
Results and Discussion
Palladium-complexed dendrimers on silica gel, up to the
third generation, were prepared according to our recently
published procedure.[19a] Briefly, Michael-type addition and
amidation reactions were used to construct dendrimers im-
mobilized on silica gel, followed by phosphonation of the
dendrimers with diphenylphosphinomethanol. The resulting
phosphonated dendrimers were then complexed with di-
chlorobis(benzonitrile)palladium(II) to give the dendritic
catalysts G0-Pd–G3-Pd (Figure 1).[20] The induced coupled
plasma (ICP) results showed that the palladium contents of
G0-Pd, G1-Pd, G2-Pd, and G3-Pd are 0.57, 0.80, 0.52, and
0.29 mmolgÀ1, respectively.
The intramolecular cyclocarbonylation of various iodinat-
ed arylamines 1[20] was used for the synthesis of twelve-
membered ring fused heterocycles 2 with G1-Pd as the cata-
lyst. Typically, a mixture of 1 mmol of iodinated arylamine 1
in 25 mL of toluene, in the
Figure 1. Structure of palladium-complexed dendrimer on silica G1-Pd.
widely employed tactic to circumvent metabolism issues
arising from the oxidation of the aromatic rings.[21] In this
regard, the fluoro-containing substrate 1d was allowed to
react with carbon monoxide in the presence of G1-Pd. As
expected, this process occurred smoothly and gave the de-
sired tricyclic heterocycle 2d in 87% yield (Table 1,
entry 4). The presence of a strongly electron-donating me-
thoxy group on the aromatic ring, the iodinated arylamine
presence of 1.5 mmol of diiso-
Table 1. Synthesis of twelve-membered ring fused heterocycles by G1-Pd-catalyzed intramolecular cyclocarbo-
nylation of iodinated arylamines 1.[a]
propylethylamine
(DIPEA)
and 15 mg of G1-Pd, was treat-
ed with 100 psi of carbon mon-
oxide at 808C for 22 h, and the
results are listed in Table 1.
The dendritic catalyst G1-Pd
was found to be highly active,
irrespective of the electronic
nature of the substituents on
the aromatic rings. Thus, iodi-
Entry
1
Substrate
Product
Yield [%][b]
92
2
3
4
5
6
88
90
87
83
76
nated arylamines
1 bearing
either electron-donating or
electron-withdrawing groups
on the aromatic rings were
readily converted to the corre-
sponding tricyclic heterocycles
2 in good to excellent yields.
For example, the reaction of
substrate 1a gave 92% yield
of the desired twelve-mem-
bered
ring
2a
(Table 1,
entry 1). The iodinated aryl-
amines 1b and c, which con-
tain methyl and chloro sub-
stituents, underwent the intra-
molecular cyclocarbonylation
reactions, and the correspond-
ing products 2b and 2c were
obtained in 88 and 90% yield,
respectively (Table 1, entries 2
and 3). In the realm of drug
design, introduction of a fluo-
ride atom into molecules is a
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5909

H. Alper and S.-M. Lu
G1-Pd as the catalyst. The
sulfur atom did not have any
influence on this process, af-
Table 1. (Continued)
Entry
Substrate
Product
Yield [%][b]
fording
the
corresponding
twelve-membered rings 2i–k in
86, 91, and 82% yields, respec-
tively (Table 1, entries 9–11).
Encouraged by these excit-
ing results, we then expanded
the scope of the intramolecular
cyclocarbonylation reactions to
the preparation of larger ring
(13–18) fused heterocycles in
the presence of G1-Pd. As can
be seen from Table 2, the den-
dritic catalyst was very effi-
cient in all cases. Again, the re-
actions of iodinated arylamines
3[20] bearing electron-donating
or electron-withdrawing sub-
stituents on the aromatic rings
gave the desired tricyclic het-
erocycles 4 in good to excellent
7
81
8[c]
83
86
91
82
9
10
11
yields. Importantly,
a broad
array of functional groups,
such as methyl, fluoro, chloro,
trifluoromethyl, methoxy, and
methoxycarbonyl, are compati-
ble with this process. For in-
stance, treatment of the iodi-
nated arylamines 3g and j with
[a] 1 mmol 1, 15 mg G1-Pd, 1.5 mmol DIPEA, 25 mL toluene, 100 psi CO, 808C and 22 h. [b] Isolated yield.
[c] Run at 1208C.
1e, also resulted in the intramolecular cyclocarbonylation
reaction, affording the corresponding twelve-membered ring
2e in 83% yield (Table 1, entry 5). It is noteworthy that
strongly electron-withdrawing substituents such as acetyl
and methoxycarbonyl groups on the aromatic rings, which
act as useful handles for further functional transformation,
can tolerate this process under the same reaction conditions,
although a slightly lower yield was obtained in the case of
1 f (Table 1, entries 6 and 7).
In comparison with iodinated arylamines, brominated ar-
ylamines are less reactive for the intramolecular cyclocarbo-
nylation reaction, but they are very attractive due to lower
cost and more readily available. We were interested in de-
Figure 2. X-ray crystal structure of 2h.
termining whether the brominated arylamine 1h could be
utilized as a substrate for this transformation. The intramo-
lecular cyclocarbonylation of 1h was thus carried out under
the reaction conditions established for iodinated arylamines,
and 65% conversion was achieved at 808C. Gratifyingly, in-
creasing the reaction temperature to 1208C gave full conver-
sion to the desired tricyclic heterocycle 2h in 83% isolated
yield (Table 1, entry 8), and its X-ray crystal structure is
shown in Figure 2.[22] Sulfur-containing compounds have
long been known to act as a poison for transition-metal cat-
alysts because of their strong coordinating and absorptive
properties. Nevertheless, the iodinated arylamines 1i–k facil-
itate the intramolecular cyclocarbonylation reactions with
carbon monoxide furnished the corresponding fifteen-mem-
bered ring 4g and sixteen-membered ring 4j in 80 and 75%
yields, respectively (Table 2, entries 7 and 10). Sulfur-con-
taining substrates are also viable partners, and one can iso-
late the desired tricyclic heterocycles in good yields. Specifi-
cally, the iodinated arylamine 3p was subjected to the stan-
dard reaction conditions, and G1-Pd catalyzed cyclocarbony-
lation gave the corresponding eighteen-membered ring 4p
in 72% yield (Table 2, entry 16), whose structure was unam-
biguously confirmed by its X-ray diffraction analysis
(Figure 3).[23] The above examples further illustrate the effi-
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Synthesis of Large Ring Macrocycles
FULL PAPER
Table 2. Synthesis of thirteen- to eighteen-membered ring fused heterocycles by G1-Pd-catalyzed intramolecu-
lar cyclocarbonylation of iodinated arylamines 3.[a]
ty, and the intramolecular cy-
clocarbonylation reaction was
conducted for five consecutive
runs in 100–95% conversions
(Table 3, entries 1–5). As seen
from Table 1, the recyclability
of G1-Pd proved to be best.
The dendritic catalyst could be
recovered by simple filtration
in air and reused up to the
eighth cycle with only a slight
loss of activity (Table 3, en-
tries 6–13). There were 100–
91% conversions from the first
cycle to the fifth cycle when
G2-Pd was examined as the
catalyst under the same reac-
tion conditions (Table 3, en-
tries 14–18). G3-Pd showed
low recyclability, and the fifth
cycle gave 43% conversion
(Table 3, entries 19–23). This
was attributed to steric crowd-
ing at the higher generation. In
order to relieve steric crowding
and allow for increased cata-
lyst loading, G3(C6)-Pd was
prepared by the use of 1,6-dia-
minohexane in place of the
ethylenediamine linker, with
Entry
Substrate
Product
Yield [%][b]
1
2
3
3a n=1, X=O, R =CH3
3b n=1, X=S, R =H
3c n=1, X=S, R =Cl
4a
4b
4c
83
87
91
4
5
6
3d n=2 , X=O, R =F
3e n=2 , X=S, R =H
3 f n=2 , X=S, R =CF3
4d
4e
4 f
88
85
82
7
8
9
3g n=3, X=O, R =CH3O
3h n=3, X=S, R =Cl
3i n=3, X=S, R =CF3
4g
4h
4i
80
87
83
10
11
12
3j n=4, X=O, R =CO2CH3
3k n=4, X=S, R =H
3l n=4, X=S, R =CF3
4j
4k
4l
75
83
79
13
14
3m n=5, X=S, R =Cl
3n n=5, X=S, R =CF3
4m
4n
83
78
0.57 mmolgÀ1
palladium.[20]
Indeed, the recyclability of
G3(C6)-Pd was comparable to
that observed employing G0-
Pd as the catalyst (Table 3, en-
tries 1–5 and entries 24–28),
and substantially superior to
that of G3-Pd. Note that these
dendritic catalysts are very
stable in a chemical sense since
they can be stored in air at
room temperature for months.
15
16
3o n=6, X=S, R =H
3p n=6, X=S, R =Cl
4o
4p
70
72
[a] 1 mmol 3, 15 mg G1-Pd, 1.5 mmol DIPEA, 25 mL toluene, 100 psi CO, 808C and 22 h. [b] Isolated yield.
ciency and generality of this protocol for the construction of
large ring fused heterocycles.
The key property of metallodendrimers is their recovery
Conclusion
and reuse, an essential perspective for green chemistry in-
volving both ecological and economical considerations. We
chose the intramolecular cyclocarbonylation of 2-[4-(2-iodo-
phenoxy)butoxy]aniline (1a) as the model reaction for the
evaluation of the activity and recyclability of different den-
dritic catalysts G0-Pd–G3-Pd under the standard conditions,
and the results are presented in Table 3. The dendritic spe-
cies G0-Pd–G3-Pd were found to be highly active catalysts
for this transformation. All of the first cycles afforded com-
plete conversions of the iodinated arylamine to the tricyclic
heterocycle. For example, G0-Pd exhibited good recyclabili-
In summary, the intramolecular cyclocarbonylation reaction
with recyclable palladium-complexed dendrimers on silica
gel is a powerful method for the synthesis of oxygen-, nitro-
gen-, or sulfur-containing macrocycles. The heterogeneous
dendritic catalysts display high activity in these transforma-
tions, affording the desired tricyclic heterocycles with twelve
to eighteen members in good to excellent yields. Moreover,
these dendritic catalysts have competitive advantages in that
they can be easily recovered by simple filtration in air and
reused for up to eight cycles with only a slight loss of activity.
Chem. Eur. J. 2007, 13, 5908 – 5916
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H. Alper and S.-M. Lu
Experimental Section
General methods: All solvents were dried and distilled under nitrogen
prior to use, other chemicals were used as received without further purifi-
cation. Analytical thin-layer chromatography (TLC) was performed on
E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized with
a 254 nm ultraviolet lamp. Flash column chromatography was undertaken
with silica gel (60, 230–400 mesh) supplied by Silicycle (Quebec,
Canada). GC analyses were carried out using an Agilent 6850 series chro-
matograph. IR spectra were obtained with a Shimadzu FTIR-8400S spec-
trometer. Mass spectra were determined using a VG 7070E spectrometer.
Solution 1H NMR and 13C NMR spectra were recorded in CDCl3 or
[D6]DMSO on a Varian Inova 500 MHz spectrometer. Chemical shifts
(d) were reported in ppm with the solvent signals as reference, and cou-
pling constants (J) were given in Hertz (Hz). Solid-state 13C NMR and
13P NMR spectra were measured with a Bruker ASX-200 spectrometer.
ICP analyses were done by Galbraith Laboratories, Knoxville, TN. Melt-
ing points are uncorrected.
CAUTION: Carbon monoxide, a powerful asphyxiant, should be used
with care. To use and work with carbon monoxide safely, reactions must
be carried out in a properly working fumehood with carbon monoxide
detectors installed nearby.
Figure 3. X-ray crystal structure of 4p.
General procedure for the intramolecular cyclocarbonylation reaction: A
glass liner containing the substrate (1 mmol), dendritic catalyst (15 mg),
diisopropylethylamine (1.5 mmol) and toluene (25 mL) was placed in a
45 mL autoclave equipped with a magnetic stirring bar. The autoclave
was flushed three times with carbon monoxide and pressurized to 100 psi.
The autoclave was then placed in an oil bath preset to the desired tem-
perature on a stirring hot plate (808C for iodides and 1208C for bro-
mides). After 22 h, the autoclave was removed from the oil bath and
cooled to room temperature prior to the release of excess carbon monox-
ide. The reaction mixture was filtered and washed with dichloromethane.
The combined solvent was evaporated in vacuo, and the residue was puri-
fied by silica gel chromatography with a mixture of hexane and ethyl ace-
tate as the eluant to afford the product. The recovered catalyst was
reused for subsequent cycles.
Table 3. Intramolecular cyclocarbonylation of 2-[4-(2-iodophenoxy)bu-
toxy)]aniline with different palladium-complexed dendrimers on silica
gel.[a]
Entry
Catalyst
Cycle
1
Conversion[b] [%]
100
1
2
G0-Pd
G0-Pd
2100
3
4
G0-Pd
G0-Pd
3
4
98
97
6,7,8,9-Tetrahydro-15H-5,10-dioxa-15-azadibenzo[a,e]cyclododecen-16-
N
one (2a): 92% yield; 1H NMR (500 MHz, [D6]DMSO): d=11.34 (s, 1H),
8.30 (dd, J=1.5, 8.0 Hz, 1H), 8.08 (dd, J=1.5, 7.5 Hz, 1H), 7.55 (dt, J=
1.5, 8.0 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 7.14–7.03 (m, 4H), 4.30 (t, J=
5.0 Hz, 2H), 4.05 (t, J=5.5 Hz, 2H), 2.15–2.13 (m, 2H), 2.01–1.99 ppm
(m, 2H); 13C NMR (125 MHz, [D6]DMSO): d=162.52, 157.54, 148.85,
134.45, 132.02, 131.95, 124.41, 124.25, 121.78, 121.49, 119.69, 119.56,
5
G0-Pd
5
95
6
G1-Pd
1
100
7
G1-Pd
2100
8
9
G1-Pd
G1-Pd
3
4
99
98
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
G1-Pd
G1-Pd
G1-Pd
G1-Pd
G2-Pd
G2-Pd
G2-Pd
G2-Pd
G2-Pd
G3-Pd
G3-Pd
G3-Pd
G3-Pd
G3-Pd
5
6
7
8
1
298
3
4
5
1
285
3
4
5
1
2100
3
4
5
98
96
96
95
113.48, 72.37, 70.91, 28.59, 25.13 ppm; IR (neat): n˜ =1660 cmÀ1
; MS
(70 eV, EI): m/z: 283 [M +]; HRMS (70 eV, EI): m/z: calcd for
C17H17NO3: 283.1208; found: 283.1189.
13-Methyl-6,7,8,9-tetrahydro-15H-5,10-dioxa-15-azadibenzo[a,e]cyclodo-
N
100
decen-16-one (2b): 88% yield; m.p. 89–908C; 1H NMR (500 MHz,
[D6]DMSO): d=11.23 (s, 1H), 8.17 (d, J=1.0 Hz, 1H), 8.08 (dd, J=1.5,
8.0 Hz, 1H), 7.54 (dt, J=2.0, 8.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.12
(t, J=7.5 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.82(dd, J=1.5, 8.0 Hz, 1H),
4.28 (t, J=5.0 Hz, 2H), 3.98 (t, J=5.5 Hz, 2H), 2.27 (s, 3H), 2.13–2.11
(m, 2H), 1.99–1.97 ppm (m, 2H); 13C NMR (125 MHz, [D6]DMSO): d=
162.43, 157.49, 146.69, 134.41, 133.50, 131.95, 131.89, 124.68, 121.77,
121.48, 120.31, 119.89, 113.40, 72.48, 70.79, 28.66, 24.88, 21.66 ppm; IR
(neat): n˜ =1665 cmÀ1; MS (70 eV, EI): m/z: 297 [M +]; HRMS (70 eV,
EI): m/z: calcd for C18H19NO3: 297.1365; found: 297.1343.
96
93
91
100
73
62
43
G3(C6)-Pd
G3(C6)-Pd
G3(C6)-Pd
G3(C6)-Pd
G3(C6)-Pd
100
13-Chloro-6,7,8,9-tetrahydro-15H-5,10-dioxa-15-azadibenzo[a,e]cyclodo-
U
decen-16-one (2c): 90% yield; m.p. 144–1458C; 1H NMR (500 MHz,
[D6]DMSO): d=11.40 (s, 1H), 8.32(d, J=2.5 Hz, 1H), 8.06 (dd, J=2.0,
7.5 Hz, 1H), 7.56 (dt, J=1.5, 8.0 Hz, 1H), 7.20–7.06 (m, 4H), 4.28 (t, J=
5.0 Hz, 2H), 4.04 (t, J=5.5 Hz, 2H), 2.13–2.10 (m, 2H), 2.01–1.96 ppm
(m, 2H); 13C NMR (125 MHz, [D6]DMSO): d=162.79, 157.61, 147.66,
134.78, 133.09, 131.95, 127.86, 123.79, 121.85, 120.98, 120.93, 119.03,
97
97
96
[a] 1 mmol 2-[4-(2-iodophenoxy)butoxy]aniline, 15 mg catalyst, 1.5 mmol
DIPEA, 25 mL toluene, 100 psi CO, 808C and 22 h. [b] Determined by
1
GC and H NMR.
113.55, 72.75, 70.96, 28.46, 25.06 ppm; IR (neat): n˜ =1662cm À1
; MS
(70 eV, EI): m/z: 317 [M +]; HRMS (70 eV, EI): m/z: calcd for
C17H16ClNO3: 317.0819; found: 317.0801.
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Chem. Eur. J. 2007, 13, 5908 – 5916

Synthesis of Large Ring Macrocycles
FULL PAPER
13-Fluoro-6,7,8,9-tetrahydro-15H-5,10-dioxa-15-azadibenzo
G
[D6]DMSO): d=10.71 (s, 1H), 8.74 (d, J=8.0 Hz, 1H), 8.11 (dd, J=1.5,
8.0 Hz, 1H), 7.64–7.57 (m, 2H), 7.26 (d, J=8.5 Hz, 1H), 7.15–7.12(m,
2H), 4.30 (t, J=5.0 Hz, 2H), 3.04 (t, J=6.0 Hz, 2H), 2.15–2.12 (m, 2H),
1.93–1.87 ppm (m, 2H); 13C NMR (125 MHz, [D6]DMSO): d=163.54,
157.61, 142.51, 138.37, 135.20, 135.00, 132.70, 124.08, 121.90, 121.52,
121.01, 119.91, 113.61, 71.00, 35.58, 26.45, 25.46 ppm; IR (neat): n˜ =
1666 cmÀ1; MS (70 eV, EI): m/z: 333 [M +]; HRMS (70 eV, EI): m/z:
calcd for C17H16ClNO2S: 333.0590; found: 333.0568.
decen-16-one (2d): 87% yield; m.p. 122–1238C; 1H NMR (500 MHz,
[D6]DMSO): d=11.39 (s, 1H), 8.12–8.07 (m, 2H), 7.58 (dt, J=1.5,
8.0 Hz, 1H), 7.25–7.12 (m, 3H), 6.86 (dt, J=3.0, 8.5 Hz, 1H), 4.31 (t, J=
5.0 Hz, 2H), 4.03 (t, J=5.5 Hz, 2H), 2.15–2.13 (m, 2H), 2.00–1.98 ppm
(m, 2H); 13C NMR (125 MHz, [D6]DMSO): d=162.82, 158.58 (d, J=
235.6 Hz), 157.61, 145.10 (d, J=1.9 Hz), 134.79, 133.18 (d, J=12.5 Hz),
131.98, 121.86, 121.37 (d, J=9.5 Hz), 120.91, 113.49, 110.06 (d, J=
23.9 Hz), 106.76 (d, J=28.6 Hz), 72.93, 70.84, 28.58, 24.79 ppm; IR
(neat): n˜ =1658 cmÀ1; MS (70 eV, EI): m/z: 301 [M +]; HRMS (70 eV,
EI): m/z: calcd for C17H16FNO3: 301.1114; found: 301.1102.
13-Trifluoromethyl-6,7,8,9-tetrahydro-15H-5-oxa-10-thia-15-azadibenzo-
[a,e]cyclododecen-16-one (2k): 82% yield; m.p. 137–138 8C; 1H NMR
(500 MHz, [D6]DMSO): d=10.76 (s, 1H), 9.03 (s, 1H), 8.11 (dd, J=1.5,
7.5 Hz, 1H), 7.82(d, J=8.0 Hz, 1H), 7.58 (dt, J=2.0, 7.5 Hz, 1H), 7.38
(d, J=8.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.14 (d, J=7.5 Hz, 1H), 4.30
(t, J=5.0 Hz, 2H), 3.10 (t, J=6.0 Hz, 2H), 2.15–2.12 (m, 2H), 1.94–
1.90 ppm (m, 2H); 13C NMR (125 MHz, [D6]DMSO): d=163.76, 157.64,
142.02, 137.92, 135.05, 132.70, 130.86 (q, J=32.5 Hz), 127.56, 124.57 (q,
J=270.9 Hz), 121.91, 120.93, 120.54 (q, J=3.8 Hz), 116.40 (q, J=3.9 Hz),
13-Methoxy-6,7,8,9-tetrahydro-15H-5,10-dioxa-15-azadibenzo[a,e]cyclo-
dodecen-16-one (2e): 83% yield; m.p. 108–1098C; 1H NMR (500 MHz,
[D6]DMSO): d=11.23 (s, 1H), 8.09 (dd, J=1.5, 8.0 Hz, 1H), 7.99 (d, J=
3.0 Hz, 1H), 7.55 (dt, J=1.5, 8.5 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 7.12
(t, J=7.5 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.58 (dd, J=3.0, 8.5 Hz, 1H),
4.30 (t, J=5.0 Hz, 2H), 3.96 (t, J=5.5 Hz, 2H), 3.72 (s, 3H), 2.14–2.12
(m, 2H), 1.98–1.95 ppm (m, 2H); 13C NMR (125 MHz, [D6]DMSO): d=
162.62, 157.53, 156.19, 142.57, 134.57, 132.98, 131.99, 121.80, 121.40,
121.20, 113.38, 108.71, 106.03, 72.81, 70.71, 55.99, 28.73, 24.60 ppm; IR
(neat): n˜ =1661 cmÀ1; MS (70 eV, EI): m/z: 313 [M +]; HRMS (70 eV,
EI): m/z: calcd for C18H19NO4: 313.1314; found: 313.1305.
113.58, 71.07, 35.21, 26.47, 25.16 ppm; IR (neat): n˜ =1663 cmÀ1
; MS
(70 eV, EI): m/z: 367 [M +]; HRMS (70 eV, EI): m/z: calcd for
C18H16F3NO2S: 367.0854; found: 367.0848.
20-Methyl-10,16-dioxa-2-azatricyclo[15.4.0.04,9]heneicosa-1(17),4(9),5,7,
18,20-hexaen-3-one (4a): 83% yield; m.p. 80–818C; 1H NMR (500 MHz,
[D6]DMSO): d=10.65 (s, 1H), 8.40 (d, J=1.5 Hz, 1H), 8.11 (dd, J=1.5,
7.5 Hz, 1H), 7.52(dt, J=1.5, 8.0 Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 7.12–
7.06 (m, 2H), 6.82 (dd, J=1.5, 8.0 Hz, 1H), 4.17–4.12 (m, 4H), 2.24 (s,
3H), 1.93–1.90 (m, 2H), 1.82–1.78 ppm (m, 4H); 13C NMR (125 MHz,
[D6]DMSO): d=162.82, 157.58, 146.02, 134.39, 132.31, 131.23, 130.8,
124.47, 121.61, 121.42, 120.64, 115.51, 113.59, 69.57, 68.70, 27.23, 26.79,
21.59, 21.56 ppm; IR (neat): n˜ =1665 cmÀ1; MS (70 eV, EI): m/z: 311 [M +
]; HRMS (70 eV, EI): m/z: calcd for C19H21NO3: 311.1521; found:
311.1504.
10-Oxa-16-thia-2-azatricyclo[15.4.0.04,9]heneicosa-1(17),4(9),5,7,18,20-
hexaen-3-one (4b): 87% yield; m.p. 103–1048C; 1H NMR (500 MHz,
[D6]DMSO): d=10.28 (s, 1H), 8.50 (d, J=8.0 Hz, 1H), 7.96 (dd, J=1.5,
7.5 Hz, 1H), 7.65 (d, J=7.5 Hz, 1H), 7.53 (dt, J=1.5, 8.5 Hz, 1H), 7.38
(t, J=8.0 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 7.12–7.08 (m, 2H), 4.15 (t,
J=5.0 Hz, 2H), 2.90 (t, J=6.0 Hz, 2H), 1.85–1.81 (m, 2H), 1.75–1.70 (m,
2H), 1.61–1.57 ppm (m, 2H); 13C NMR (125 MHz, [D6]DMSO): d=
163.95, 157.26, 141.20, 137.52, 134.25, 132.50, 130.36, 125.00, 124.26,
122.69, 121.63, 121.28, 113.75, 69.92, 38.19, 27.13, 26.46, 23.63 ppm; IR
(neat): n˜ =1660 cmÀ1; MS (70 eV, EI): m/z: 313 [M +]; HRMS (70 eV,
EI): m/z: calcd for C18H19NO2S: 313.1136; found: 313.1119.
20-Chloro-10-oxa-16-thia-2-azatricycl[15.4.0.04,9]heneicosa-1(17),4(9),5,7,
18,20-hexaen-3-one (4c): 91% yield; m.p. 133–1348C; 1H NMR
(500 MHz, [D6]DMSO): d=10.37 (s, 1H), 8.62(d, J=2.0 Hz, 1H), 7.95
(dd, J=1.5, 7.5 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.57 (dt, J=1.5, 8.0 Hz,
1H), 7.24–7.18 (m, 2H), 7.12 (t, J=7.5 Hz, 1H), 4.19 (t, J=5.0 Hz, 2H),
2.94 (t, J=6.0 Hz, 2H), 1.88–1.84 (m, 2H), 1.76–1.71 (m, 2H), 1.64–
1.60 ppm (m, 2H); 13C NMR (125 MHz, [D6]DMSO): d=163.34, 157.36,
142.24, 138.88, 134.75, 134.62, 132.29, 124.71, 123.09, 122.27, 121.76,
120.55, 113.95, 70.15, 38.18, 26.91, 26.43, 23.68 ppm; IR (neat): n˜ =
1658 cmÀ1; MS (70 eV, EI): m/z: 347 [M +]; HRMS (70 eV, EI): m/z:
calcd for C18H18ClNO2S: 347.0747; found: 347.0728.
13-Acetyl-6,7,8,9-tetrahydro-15H-5,10-dioxa-15-azadibenzo[a,e]cyclodo-
R
decen-16-one (2 f): 76% yield; m.p. 171–1728C; 1H NMR (500 MHz,
[D6]DMSO): d=11.56 (s, 1H), 8.80 (d, J=2.0 Hz, 1H), 8.08 (dd, J=1.5,
7.5 Hz, 1H), 7.72(dd, J=2.0, 8.0 Hz, 1H), 7.57 (dt, J=2.0, 8.5 Hz, 1H),
7.23–7.18 (m, 2H), 7.14 (t, J=7.5 Hz, 1H), 4.30 (t, J=5.0 Hz, 2H), 4.16
(t, J=5.5 Hz, 2H), 2.54 (s, 3H), 2.15–2.13 (m, 2H), 2.06–2.02 ppm (m,
2H); 13C NMR (125 MHz, [D6]DMSO): d=197.29, 162.64, 157.66, 152.67,
134.58, 132.19, 131.87, 131.15, 125.74, 121.83, 121.45, 118.46, 116.49,
113.67, 72.07, 71.31, 28.24, 27.25, 25.81 ppm; IR (neat): n˜ =1685,
1660 cmÀ1; MS (70 eV, EI): m/z: 32 5 M[ +]; HRMS (70 eV, EI): m/z:
calcd for C19H19NO4: 325.1314; found: 325.1296.
16-Oxo-6,7,8,9,15,16-hexahydro-5,10-dioxa-15-azadibenzo[a,e]cyclodode-
A
cene-13-carboxylic methyl ester (2g): 81% yield; m.p. 169–1708C;
1H NMR (500 MHz, [D6]DMSO): d=11.56 (s, 1H), 8.82(d, J=2.0 Hz,
1H), 8.06 (dd, J=1.5, 8.0 Hz, 1H), 7.66 (dd, J=2.0, 8.0 Hz, 1H), 7.56 (dt,
J=1.5, 8.0 Hz, 1H), 7.20–7.12 (m, 3H), 4.28 (t, J=5.0 Hz, 2H), 4.14 (t,
J=5.5 Hz, 2H), 3.83 (s, 3H), 2.13–2.11 (m, 2H), 2.04–2.01 ppm (m, 2H);
13C NMR (125 MHz, [D6]DMSO): d=166.60, 162.60, 157.65, 152.58,
134.58, 131.86, 131.06, 126.09, 124.34, 121.80, 121.38, 119.67, 116.58,
113.63, 71.97, 71.31, 52.73, 28.22, 25.80 ppm; IR (neat): n˜ =1680,
1663 cmÀ1; MS (70 eV, EI): m/z: 341 [M +]; HRMS (70 eV, EI): m/z:
calcd for C19H19NO5: 341.1263; found: 341.1248.
16-Oxo-6,7,8,9,15,16-hexahydro-5,10-dioxa-15-azadibenzo[a,e]cyclodode-
T
cene-12-carboxylic methyl ester (2h): 83% yield; m.p. 163–1648C;
1H NMR (500 MHz, [D6]DMSO): d=11.64 (s, 1H), 8.39 (d, J=8.5 Hz,
1H), 8.08 (dd, J=1.5, 8.0 Hz, 1H), 7.72(dd, J=1.0, 8.5 Hz, 1H), 7.61–
7.56 (m, 2H), 7.22 (d, J=8.5 Hz, 1H), 7.14 (t, J=7.5 Hz, 1H), 4.30 (t, J=
5.0 Hz, 2H), 4.12 (t, J=5.5 Hz, 2H), 3.81 (s, 3H), 2.15–2.13 (m, 2H),
2.04–2.01 ppm (m, 2H); 13C NMR (125 MHz, [D6]DMSO): d=166.27,
162.81, 157.69, 148.44, 136.12, 134.85, 132.01, 125.84, 125.03, 121.86,
121.01, 119.02, 118.68, 113.62, 72.52, 71.12, 52.72, 28.40, 25.32 ppm; IR
(neat): n˜ =1683, 1665 cmÀ1; MS (70 eV, EI): m/z: 341 [M+ ]; HRMS
(70 eV, EI): m/z: calcd for C19H19NO5: 341.1263; found: 341.1251.
15-Fluoro-6,7,8,9,10,11-hexahydro-17H-5,12-dioxa-17-azadibenzo[a,e]cy-
G
clotetradecen-18-one (4d): 88% yield; m.p. 147–1488C; 1H NMR
(500 MHz, [D6]DMSO): d=10.08 (s, 1H), 8.50 (dd, J=3.0, 7.0 Hz, 1H),
8.13 (dd, J=1.5, 7.5 Hz, 1H), 7.55 (dt, J=1.5, 8.0 Hz, 1H), 7.21 (d, J=
8.0 Hz, 1H), 7.12–7.04 (m, 2H), 6.88 (dt, J=3.0, 8.5 Hz, 1H), 4.21 (t, J=
5.0 Hz, 2H), 4.12 (t, J=5.0 Hz, 2H), 1.92–1.88 (m, 4H), 1.83–1.77 (m,
2H), 1.69–1.66 ppm (m, 2H); 13C NMR (125 MHz, [D6]DMSO): d=
163.76, 157.49, 156.23 (d, J=231.9 Hz), 145.02 (d, J=1.9 Hz), 134.78,
132.82, 128.89 (d, J=11.4 Hz), 121.59, 120.68, 113.45, 112.35 (d, J=
8.5 Hz), 109.91 (d, J=23.0 Hz), 108.40 (d, J=29.5 Hz), 72.14, 69.73,
27.76, 27.32, 25.36, 25.16 ppm; IR (neat): n˜ =1663 cmÀ1; MS (70 eV, EI):
m/z: 32 9 [M +]; HRMS (70 eV, EI): m/z: calcd for C19H20FNO3: 329.1427;
found: 329.1411.
6,7,8,9-Tetrahydro-15H-5-oxa-10-thia-15-azadibenzo[a,e]cyclododecen-
R
16-one (2i): 86% yield; m.p. 111–1128C; 1H NMR (500 MHz,
[D6]DMSO): d=10.65 (s, 1H), 8.66 (d, J=8.0 Hz, 1H), 8.11 (dd, J=1.0,
7.5 Hz, 1H), 7.62(d, J=7.5 Hz, 1H), 7.55 (dt, J=1.5, 8.0 Hz, 1H), 7.40
(t, J=7.5 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.12(t, J=7.5 Hz, 1H), 7.07
(d, J=7.5 Hz, 1H), 4.29 (t, J=5.0 Hz, 2H), 3.03 (t, J=6.0 Hz, 2H), 2.14–
2.12 (m, 2H), 1.91–1.86 ppm (m, 2H); 13C NMR (125 MHz, [D6]DMSO):
d=163.25, 157.48, 141.57, 137.16, 134.63, 132.68, 130.82, 124.42, 122.59,
121.80, 121.57, 120.48, 113.51, 70.90, 35.60, 26.52, 25.32 ppm; IR (neat):
n˜ =1660 cmÀ1; MS (70 eV, EI): m/z: 299 [M +]; HRMS (70 eV, EI): m/z:
calcd for C17H17NO2S: 299.0980; found: 299.0965.
13-Chloro-6,7,8,9-tetrahydro-15H-5-oxa-10-thia-15-azadibenzo
C
6,7,8,9,10,11-Hexahydro-17H-5-oxa-12-thia-17-azadibenzo
C
Chem. Eur. J. 2007, 13, 5908 – 5916
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5913

H. Alper and S.-M. Lu
10.36 (s, 1H), 8.40 (d, J=8.5 Hz, 1H), 8.00 (dd, J=1.5, 7.5 Hz, 1H), 7.60
(dd, J=1.0, 7.5 Hz, 1H), 7.52(dt, J=1.5, 8.5 Hz, 1H), 7.33 (t, J=7.5 Hz,
1H), 7.23 (d, J=8.5 Hz, 1H), 7.12–7.07 (m, 2H), 4.32 (t, J=5.5 Hz, 2H),
2.96 (t, J=5.5 Hz, 2H), 1.84–1.81 (m, 2H), 1.57–1.52ppm (m, 6H);
13C NMR (125 MHz, [D6]DMSO): d=163.89, 156.84, 140.37, 135.47,
134.19, 132.37, 129.32, 125.12, 124.98, 122.49, 121.91, 121.53, 113.82, 68.50,
36.79, 27.03, 25.42, 25.26, 23.14 ppm; IR (neat): n˜ =1665 cmÀ1; MS (70 eV,
EI): m/z: 32 7 M[ +]; HRMS (70 eV, EI): m/z: calcd for C19H21NO2S:
327.1293; found: 327.1275.
d=9.79 (s, 1H), 8.00 (dd, J=1.5, 8.0 Hz, 1H), 7.93 (dd, J=1.0, 7.0 Hz,
1H), 7.52(dt, J=1.5, 8.0 Hz, 1H), 7.47 (dd, J=1.5, 8.0 Hz, 1H), 7.24–
7.14 (m, 3H), 7.09 (t, J=7.5 Hz, 1H), 4.24 (t, J=5.0 Hz, 2H), 3.14 (t, J=
5.5 Hz, 2H), 1.88–1.83 (m, 2H), 1.53–1.49 (m, 4H), 1.37–1.26 ppm (m,
6H); 13C NMR (125 MHz, [D6]DMSO): d=164.05, 157.48, 137.35, 134.18,
132.27, 129.78, 127.85, 126.50, 125.78, 124.80, 122.21, 121.53, 113.98, 70.23,
31.98, 27.94, 26.64, 25.19, 24.52, 23.99, 23.42 ppm; IR (neat): n˜ =
1662cm À1; MS (70 eV, EI): m/z: 355 [M +]; HRMS (70 eV, EI): m/z:
calcd for C21H25NO2S: 355.1606; found: 355.1588.
15-Trifluoromethyl-6,7,8,9,10,11-hexahydro-17H-5-oxa-12-thia-17-azadi-
17-Trifluoromethyl-6,7,8,9,10,11,12,13-octahydro-19H-5-oxa-14-thia-19-
benzo[a,e]cyclotetradecen-18-one (4 f): 82% yield; m.p. 149–150 8C;
A
azadibenzo[a,e]cyclohexadecen-20-one (4l): 79% yield; m.p. 116–1178C;
G
1H NMR (500 MHz, CDCl3): d=10.66 (s, 1H), 8.99 (d, J=1.5 Hz, 1H),
8.24 (dd, J=1.5, 7.5 Hz, 1H), 7.62(d, J=8.0 Hz, 1H), 7.47 (dt, J=1.5,
8.5 Hz, 1H), 7.28 (dd, J=1.5, 8.0 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H), 7.03
(d, J=8.5 Hz, 1H), 4.37 (t, J=5.0 Hz, 2H), 3.02 (t, J=5.5 Hz, 2H), 1.96–
1.92(m, 2H), 1.75–1.65 ppm (m, 6H); 13C NMR (125 MHz, CDCl3): d=
164.18, 156.40, 140.65, 134.84, 133.35, 132.72, 130.76 (q, J=32.5 Hz),
128.43, 123.76 (q, J=270.9 Hz), 121.87, 120.10, 120.21 (q, J=3.8 Hz),
118.2(q, J=3.9 Hz), 112.10, 67.55, 36.54, 26.73, 25.01, 24.80, 22.18 ppm;
IR (neat): n˜ =1660 cmÀ1; MS (70 eV, EI): m/z: 395 [M +]; HRMS (70 eV,
EI): m/z: calcd for C20H20F3NO2S: 395.1167; found: 395.1149.
1H NMR (500 MHz, [D6]DMSO): d=9.98 (s, 1H), 8.35 (s, 1H), 8.00 (dd,
J=1.5, 8.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.56 (dt, J=1.5, 8.5 Hz,
1H), 7.47 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.5 Hz, 1H), 7.10 (t, J=7.5 Hz,
1H), 4.26 (t, J=5.0 Hz, 2H), 3.26 (t, J=5.5 Hz, 2H), 1.90–1.82 (m, 2H),
1.61–1.50 (m, 4H), 1.38–1.29 ppm (m, 6H); 13C NMR (125 MHz,
[D6]DMSO): d=164.42, 157.54, 137.30, 134.52, 133.58, 132.33, 129.72,
126.48 (q, J=32.5 Hz), 124.80 (q, J=270.0 Hz), 121.81 (q, J=3.8 Hz),
121.73, 121.59, 120.64 (q, J=3.9 Hz), 113.98, 70.40, 31.37, 27.94, 26.71,
24.50, 24.17, 23.90, 23.21 ppm; IR (neat): n˜ =1665 cmÀ1; MS (70 eV, EI):
m/z: 42 3 M[ +]; HRMS (70 eV, EI): m/z: calcd for C22H24F3NO2S:
423.1480; found: 423.1465.
22-Methoxy-10,18-dioxa-2-azatricyclo[17.4.0.04,9]tricosa-1(19),4(9),5,7,20,
22-hexaen-3-one (4g): 80% yield; 1H NMR (500 MHz, [D6]DMSO): d=
9.52(s, 1H), 7.99–7.96 (m, 2H), 7.51 (dt, J=1.5, 8.5 Hz, 1H), 7.18 (d, J=
8.5 Hz, 1H), 7.08 (t, J=7.5 Hz, 1H), 6.92(d, J=9.0 Hz, 1H), 6.62(dd,
J=3.0, 8.5 Hz, 1H), 4.20 (t, J=5.0 Hz, 2H), 4.02 (t, J=5.0 Hz, 2H), 3.69
(s, 3H), 1.78–1.75 (m, 4H), 1.59–1.47 ppm (m, 6H); 13C NMR (125 MHz,
[D6]DMSO): d=163.70, 157.11, 153.20, 143.12, 134.16, 132.39, 128.03,
122.34, 121.50, 113.65, 112.17, 109.22, 108.92, 69.99, 69.51, 56.03, 28.74,
27.49, 27.43, 26.57, 25.52 ppm; IR (neat): n˜ =1662cm À1; MS (70 eV, EI):
m/z: 355 [M +]; HRMS (70 eV, EI): m/z: calcd for C21H25NO4: 355.1784;
found: 355.1765.
22-Chloro-10-oxa-18-thia-2-azatricyclo[17.4.0.04,9]tricosa-1(19),4(9),5,7,20,
22-hexaen-3-one (4h): 87% yield; m.p. 67–688C; 1H NMR (500 MHz,
[D6]DMSO): d=10.21 (s, 1H), 8.29 (d, J=2.5 Hz, 1H), 7.96 (dd, J=1.5,
8.0 Hz, 1H), 7.59–7.52 (m, 2H), 7.26–7.19 (m, 2H), 7.09 (d, J=7.5 Hz,
1H), 4.36 (t, J=5.0 Hz, 2H), 3.03 (t, J=5.5 Hz, 2H), 1.81–1.78 (m, 2H),
1.52–1.41 ppm (m, 8H); 13C NMR (125 MHz, [D6]DMSO): d=164.25,
156.94, 140.16, 134.34, 133.99, 132.26, 132.19, 125.40, 125.15, 122.32,
122.25, 121.53, 114.00, 68.62, 34.70, 28.05, 27.13, 26.03, 25.58, 24.51 ppm;
IR (neat): n˜ =1665 cmÀ1; MS (70 eV, EI): m/z: 375 [M +]; HRMS (70 eV,
EI): m/z: calcd for C20H22ClNO2S: 375.1060; found: 375.1047.
22-Trifluoromethyl-10-oxa-18-thia-2-azatricyclo[17.4.0.04,9]tricosa-1(19),
4(9),5,7,20,22-hexaen-3-one (4i): 83% yield; m.p. 87–888C; 1H NMR
(500 MHz, [D6]DMSO): d=10.28 (s, 1H), 8.52 (s, 1H), 8.00 (dd, J=1.5,
7.5 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.52(dt, J=1.5, 8.0 Hz, 1H), 7.44
(dd, J=1.5, 8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.08 (t, J=7.5 Hz, 1H),
4.32(t, J=5.0 Hz, 2H), 3.10 (t, J=5.5 Hz, 2H), 1.79–1.74 (m, 2H), 1.56–
1.38 ppm (m, 8H); 13C NMR (125 MHz, [D6]DMSO): d=164.29, 157.17,
138.66, 134.44, 132.70, 132.26, 131.70, 127.58 (q, J=31.5 Hz), 124.72 (q,
J=270.9 Hz), 121.98 (q, J=3.9 Hz), 121.58, 121.48, 119.16 (q, J=3.8 Hz),
114.01, 68.90, 33.96, 28.29, 27.16, 25.91, 25.75, 24.58 ppm; IR (neat): n˜ =
1660 cmÀ1; MS (70 eV, EI): m/z: 409 [M +]; HRMS (70 eV, EI): m/z:
calcd for C21H22F3NO2S: 409.1323; found: 409.1301.
18-Chloro-7,8,9,10,11,12,13,14-octahydro-6H,20H-5-oxa-15-thia-20-azadi-
benzo[a,e]cycloheptadecen-21-one (4m): 83% yield; m.p. 127–1288C;
G
1H NMR (500 MHz, [D6]DMSO): d=9.82(s, 1H), 7.98–7.95 (m, 2H),
7.55 (dt, J=1.5, 8.0 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 7.24 (dd, J=2.0,
8.5 Hz, 2H), 7.09 (t, J=7.5 Hz, 1H), 4.29 (t, J=5.5 Hz, 2H), 3.08 (t, J=
6.0 Hz, 2H), 1.84–1.80 (m, 2H), 1.62–1.59 (m, 2H), 1.48–1.44 (m, 2H),
1.37–1.23 ppm (m, 8H); 13C NMR (125 MHz, [D6]DMSO): d=164.17,
157.33, 137.67, 134.41, 132.24, 130.35, 129.97, 128.80, 125.88, 124.48,
121.76, 121.51, 113.94, 69.80, 31.99, 28.96, 27.08, 26.68, 25.99, 25.56, 25.16,
24.98 ppm; IR (neat): n˜ =1660 cmÀ1; MS (70 eV, EI): m/z: 403 [M +];
HRMS (70 eV, EI): m/z: calcd for C22H26ClNO2S: 403.1373; found:
403.1358.
18-Trifluoromethyl-7,8,9,10,11,12,13,14-octahydro-6H,20H-5-oxa-15-thia-
20-azadibenzo[a,e]cycloheptadecen-21-one (4n): 78% yield; m.p. 137–
G
1388C; 1H NMR (500 MHz, CDCl3): d=9.78 (s, 1H), 8.39 (s, 1H), 8.24
(dd, J=1.5, 8.0 Hz, 1H), 7.47 (dt, J=1.5, 8.5 Hz, 1H), 7.36–7.32(m, 2H),
7.09 (t, J=7.5 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 4.28 (t, J=6.0 Hz, 2H),
3.09 (t, J=6.0 Hz, 2H), 1.96–1.91 (m, 2H), 1.79–1.74 (m, 2H), 1.59–
1.35 ppm (m, 10H); 13C NMR (125 MHz, CDCl3): d=164.13, 157.04,
135.92, 133.48, 133.37, 132.65, 127.65 (q, J=32.5 Hz), 126.51, 123.95 (q,
J=270.9 Hz), 121.46 (q, J=3.8 Hz), 121.38, 121.13, 121.08 (q, J=3.8 Hz),
112.38, 69.56, 31.61, 29.04, 26.65, 26.22, 25.44, 24.96, 24.81, 24.72 ppm; IR
(neat): n˜ =1661 cmÀ1; MS (70 eV, EI): m/z: 437 [M +]; HRMS (70 eV,
EI): m/z: calcd for C23H26F3NO2S: 437.1636; found: 437.1627.
10-Oxa-21-thia-2-azatricyclo[20.4.0.04,9]hexacosa-1(22),4(9),5,7,23,25-he-
xaen-3-one (4o): 70% yield; m.p. 87–888C; 1H NMR (500 MHz,
[D6]DMSO): d=9.97 (s, 1H), 8.09–8.04 (m, 2H), 7.53 (dt, J=2.0, 8.5 Hz,
1H), 7.38 (dd, J=1.0, 7.5 Hz, 1H), 7.25–7.07 (m, 4H), 4.30 (t, J=5.5 Hz,
2H), 3.05 (t, J=6.0 Hz, 2H), 1.91–1.83 (m, 2H), 1.65–1.59 (m, 2H), 1.40–
1.27 ppm (m, 12H); 13C NMR (125 MHz, [D6]DMSO): d=163.70, 159.95,
136.60, 134.27, 132.42, 128.46, 128.16, 126.19, 125.66, 123.73, 121.94,
121.55, 113.91, 69.40, 32.81, 27.51, 27.01, 26.20, 25.82, 25.69, 25.62, 24.90,
23.74 ppm; IR (neat): n˜ =1665 cmÀ1; MS (70 eV, EI): m/z: 383 [M +];
HRMS (70 eV, EI): m/z: calcd for C23H29NO2S: 383.1919; found:
383.1902.
25-Chloro-10-oxa-21-thia-2-azatricyclo[20.4.0.04,9]hexacosa-1(22),4(9),5,7,
23,25-hexaen-3-one (4p): 72% yield; m.p. 151–152 8C; 1H NMR
(500 MHz, CDCl3): d=10.19 (s, 1H), 8.51 (d, J=2.5 Hz, 1H), 8.24 (dd,
J=1.5, 8.0 Hz, 1H), 7.44 (dt, J=1.5, 8.0 Hz, 1H), 7.24–7.21 (m, 1H),
7.08–7.00 (m, 3H), 4.29 (t, J=7.5 Hz, 2H), 2.97 (t, J=6.5 Hz, 2H), 1.99–
1.93 (m, 2H), 1.72–1.66 (m, 2H), 1.51–1.35 ppm (m, 12H); 13C NMR
(125 MHz, CDCl3): d=163.86, 156.56, 138.26, 133.26, 132.65, 132.22,
129.61, 124.77, 124.23, 122.36, 121.72, 121.04, 112.38, 69.19, 34.23, 27.00,
26.76, 25.81, 25.46, 25.50, 24.98, 24.24, 23.25 ppm; IR (neat): n˜ =
1660 cmÀ1; MS (70 eV, EI): m/z: 417 [M +]; HRMS (70 eV, EI): m/z:
calcd for C23H28ClNO2S: 417.1529; found: 417.1512.
20-Oxo-6,7,8,9,10,11,12,13,19,20-decahydro-5,14-dioxa-19-azadibenzo-
A
106–1078C; 1H NMR (500 MHz, [D6]DMSO): d=9.79 (s, 1H), 9.02(d,
J=2.0 Hz, 1H), 8.02 (dd, J=1.5, 7.5 Hz, 1H), 7.69 (dd, J=1.5, 8.0 Hz,
1H), 7.52(dt, J=1.0, 8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.17 (d, J=
8.5 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H), 4.29–4.23 (m, 4H), 3.81 (s, 3H),
1.79–1.73 (m, 4H), 1.46–1.40 ppm (m, 8H); 13C NMR (125 MHz,
[D6]DMSO): d=166.66, 164.08, 156.85, 152.16, 134.16, 132.44, 127.96,
126.71, 122.84, 122.38, 122.03, 121.59, 114.09, 112.24, 69.15, 68.29, 52.60,
27.51, 27.00, 25.73, 25.55, 23.27, 22.78 ppm; IR (neat): n˜ =1685,
1666 cmÀ1; MS (70 eV, EI): m/z: 397 [M +]; HRMS (70 eV, EI): m/z:
calcd for C23H27NO5: 397.1889; found: 397.1871.
6,7,8,9,10,11,12,13-Octahydro-19H-5-oxa-14-thia-19-azadibenzo
C
5914
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Chem. Eur. J. 2007, 13, 5908 – 5916

Synthesis of Large Ring Macrocycles
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[20] See Supporting Information for the preparation details.
[22] CCDC-629068 (2h) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
[23] CCDC-629029 (4p) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
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Received: December 1, 2006
Published online: April 20, 2007
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